Discovery of Nanomolar DCAF1 Small Molecule Ligands.

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 µM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 µM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

Linear versus Nonlinear Muscle Networks: A Case Study to Decode Hidden Synergistic Patterns During Dynamic Lower-limb Tasks.

This paper, for the first time, compares the behaviors of nonlinear versus linear muscle networks in decoding hidden peripheral synergistic neural patterns during dynamic functional tasks. In this paper, we report a case study during which one healthy subject conducts a series of four lower limb repetitive tasks. Specifically, the paper focuses on tasks that involve the right knee joint, including walking, sit-tostand, stepping, and drop-jump. Twelve muscles were recorded using the Delsys Trigno system. The linear muscle network was generated using coherence analysis, and the nonlinear network was generated using Spearman's correlation. The results show that the degree, clustering coefficient, and global efficiency of the muscle network have the highest value among tasks in the linear domain for the walking task, while a low linear synergistic network behavior for the sit-to-stand is observed. On the other hand, the results show that the nonlinear functional muscle network decodes high connectivity (degree) and clustering coefficient and efficiency for the sit-tostand when compared with other tasks. We have also developed a two-dimensional functional connectivity plane composed of linear and nonlinear features and shown that it can span the lower-limb dynamic task space. The results of this paper for the first time highlight the importance of observing both linear and nonlinear connectivity patterns, especially for complex dynamic tasks. It should also be noted that through a simultaneous EEG recording (using BrainVision System), we have shown that, indeed, cortical activity may indirectly explain highly-connected nonlinear muscle network for the sit-to-stand task, highlighting the importance of nonlinear muscle network as a neurophysiological window of observation beyond the periphery.

Interrater Reliability of an Observational Rating Scale and Video Analysis of Yoga Poses.

CONTEXT: Yoga is increasingly popular, not only as a form of recreational exercise but also as a physician-recommended intervention for health conditions. While serious adverse effects accompanying yoga practice are rare, poses that involve upper-extremity weight-bearing have a high risk of discomfort. To better understand factors contributing to adverse effects, there is a critical need for robust instruments that objectively evaluate pose performance. The purpose of this study was to assess the interrater reliability of an observational scale developed to assess the alignment of 3 yoga poses. DESIGN: Cross-sectional experimental study. METHODS: Thirty-eight individuals were given standardized instructions and performed 3 poses (Downward Dog, Plank, and Side Plank). Lateral videos were rated by 2 raters. A rating scale evaluating the alignment of 7 regions was developed by the study team with input from yoga teachers. Descriptive statistics were used to summarize the percentage of subjects showing ideal alignment and deviations. Interrater reliability was quantified using Cohen kappa coefficient (κ). RESULTS: In Downward Dog, the prevalence of ideal alignment was 20%, 28%, and 37%, at the neck, shoulder, and back, respectively; κ ranged from .44 to .69. In Plank, the prevalence of ideal alignment was 31%, 45%, and 54% at the neck, shoulder, and back, respectively; κ ranged from .47 to .95. In Side Plank, the prevalence of ideal alignment was 16, 41%, and 24%, at the neck, shoulder, and back, respectively; κ ranged from .20 to .84. CONCLUSION: The observational scale found a high prevalence of deviations, and demonstrated fair to substantial interrater agreement.

Can We Innovatively Modify the Surgical Helmets to Protect Against the Droplets and Aerosols of COVID-19?

We tested the filtration efficiency of Stryker T5 surgical helmets with and without the addition of a filter medium. Two particle counters were used to count the particles of sizes .5 µm, 1 µm, and 5 µm, both inside and outside the Stryker T5 helmet, concurrently. The total inward leakage (TIL) for the helmet with and without the filter was zero for 5 µm particles at all time points. The TIL (3.4) for the .5 µm particles decreased significantly after application of the filter (1.7; P = .007). We recommend that an N95 should be used inside the helmet system.

Telehealth for consultation and shoulder rehabilitation: a preliminary study on the perspectives of 30 patients during the COVID-19 lockdown.

BACKGROUND: This study aimed to determine: the perspectives of the patient cohort that underwent telehealth consultation and shoulder rehabilitation during coronavirus disease 2019 (COVID-19) and the differences in the patients' perspectives with the two different telehealth video applications (apps) used in the study. METHODS: This is a prospective study carried out during the COVID lockdown period of April to July 2020. Thirty consecutive patients from the orthopedics department of a tertiary institute in India underwent their first-ever session of a video app-based (Zoom or WhatsApp) telehealth consultation with shoulder rehabilitation exercises on a handheld mobile, tablet, or laptop device. After the virtual consultation, the patients were sent a validated telehealth usability questionnaire (TUQ) to evaluate their perspectives. Scores obtained from the TUQ were the primary outcome measure. RESULTS: The study was completed by 30 patients (16 men and 14 women) with an average age of 56 years (range, 20-77 years). The patients who contacted us during the lockdown period with either a stiff shoulder or a conservatively treated shoulder fracture were included in the study. The average TUQ score was 13.6 (median, 14.5; range, 6-21) out of a maximum of 21 points. Eighty percent of the patients were satisfied and found the telehealth service useful. Use of the Zoom app scored significantly higher (median, 17; average, 15.6) than the WhatsApp app (median, 8.5; average, 9.6) (p=0.004). CONCLUSIONS: Patients who received telehealth consultation and shoulder rehabilitation were overall satisfied. Telehealth apps with advanced video calling features such as Zoom should be preferred for higher patient satisfaction.

Instability, complications, and functional outcomes after reverse shoulder arthroplasty and anatomic shoulder arthroplasty for chronic neglected shoulder dislocation: a systematic review.

Background: Chronic shoulder dislocation has been treated by either anatomic shoulder arthroplasty (ASA) or reverse shoulder arthroplasty (RSA) with encouraging results. Although good results have been reported after both the procedures, several complications such as instability and glenoid failures have also been highlighted. The aim of this study was to aggregate the results that have been reported with the use of ASA or RSA in chronic shoulder dislocation and analyze the instability rates, complication rates, and functional outcomes. Methods: A comprehensive search was performed in May 2020 using PubMed, EMBASE, and Cochrane Library databases. Studies that reported on the outcomes after either ASA or RSA for chronic anterior dislocation (CAD) or chronic posterior dislocation (CPD) were included in the systematic review. Methodologic quality was assessed using the Methodological Index for Nonrandomized Studies appraisal tool for observational studies. Results: We aggregated 13 studies that included data on 128 patients with CAD and 51 patients with CPD. The combined weighted postoperative instability rate in the CAD group was significantly higher after ASA than after RSA (P = .04). There was no significant difference in the combined weighted instability rate between ASA in the CAD group and ASA in the CPD group (P = .37). The complications of RSA in CAD included glenoid base plate loosening, humeral shaft fractures, late infection, acromion fractures, and instability. The complications of the ASA in CAD and CPD included glenoid loosening and erosions, severe pain necessitating revision, severe superior migration of the head, redislocation with rupture of the cuff tendons, bone graft migration, instability, and 2 cases of neuropathies (median nerve and axillary nerve) that eventually resolved. Conclusion: Postoperative instability was significantly more common after ASA than after RSA for chronic shoulder dislocations, but both RSA and ASA had a high complication rate in CAD. Shoulder arthroplasty improved the range of motion, functional outcomes, and pain in patients with chronic shoulder dislocation.

Results and complications of head-preserving techniques in chronic neglected shoulder dislocation: a systematic review.

BACKGROUND: Humeral head-preserving procedures may be needed for chronic neglected shoulder dislocation because the presenting age of the patient is often reported to be less than 45 years. The aim of this systematic review was to evaluate the results of the various head-preserving procedures for chronic anterior dislocation (CAD) and chronic posterior dislocation (CPD). This review also aimed to evaluate the results of conservative neglect for CAD. METHODS: PubMed, Embase, and Cochrane library databases were queried for studies that reported on results of head-preserving procedures for CAD or CPD and for studies that reported on the results of conservative neglect for CAD. Case reports, review articles, acute dislocations, and fracture-dislocations were excluded. The results of the different techniques were pooled for further evaluation. RESULTS: Seventeen studies were selected for qualitative analysis. These were further subdivided into 9 studies for the CAD group and 11 studies for the CPD group. In the CAD intervention group, 53 shoulders in 7 studies were managed by 5 different head-preserving techniques. The choice of procedure to stabilize the shoulder after open reduction varied between coracoid transfer, capsulolabral repair, remplissage, and Putti-Platt procedure and acromiohumeral K-wire fixation. High resubluxation rates and early arthrosis were reported after open reduction techniques for CAD. In the CAD conservative group, 8 shoulders in 2 studies were managed by conservative methods. In the CPD group, the 2 most common techniques, McLaughlin or modified McLaughlin and bone grafting, were used to treat 74 shoulders in 7 studies and showed good functional outcomes. CONCLUSION: The choice of open reduction and stabilization technique for CAD was highly variable between the different studies and led to a wide variation in the reported outcomes with a high number of complications such as resubluxation and early arthrosis. The conservative treatment of CAD led to poor functional results. The choice of treatment for CPD was mostly between 2 techniques-McLaughlin and modified McLaughlin reconstruction or the bone graft reconstruction-and they consistently led to good functional outcomes with less complications.

Geometric analysis of the humeral head and glenoid in the Indian population and its clinical significance.

BACKGROUND: Total anatomic and reverse shoulder prostheses are designed to match the dimensions of the native bony anatomy. Chinese and Japanese bony dimensions of the shoulder have been found to be different from that of the Caucasian population. We hypothesized that the geometric dimensions of the humeral head and glenoid in the Indian population would also be different from that of the Caucasian population. METHOD: Fifty patients underwent computerized tomographic scans of their normal shoulders. We calculated the superoinferior (SI) diameter of the humeral head, anteroposterior diameter of the humeral head, radius of curvature of the humeral head, humeral head retroversion, humeral head thickness, inclination angle, critical shoulder angle, greater tuberosity angle, glenoid width, glenoid length, radius of curvature of the glenoid, glenoid inclination angle, and glenoid version. RESULTS: The radius of curvature of the humeral head averaged 22.9 ± 1.7 mm, the articular surface thickness 17.1 ± 1.6 mm, and the SI diameter 42.3 ± 3 mm. The SI diameter strongly correlated with the thickness (r = 0.617, P = .001). The anteroposterior/SI articular surface diameter ratio averaged 0.9 ± 0.9, the articular surface thickness/radius of curvature ratio 0.7 ± 0.9, the inclination angle 133.8 ± 6.4, and the retroversion angle 33.5° ± 8.5°. The radius of curvature of the glenoid averaged 23.3 ± 3.4 mm, the glenoid width 24.0 ± 2 mm, the SI length 31.3 ± 2.2 mm, the glenoid inclination angle 78.7° ± 4.8°, and the glenoid retroversion 1.8° ± 3.8°. DISCUSSION: Compared with the Western population, our cohort had a smaller humeral radius of curvature (P = .04), smaller articular surface diameter (P = .001), smaller inclination angle (P = .003), larger retroversion angle of the humeral head (P < .001), and smaller glenoid length and width (P < .0001). Most of the implant companies did not have smaller sized combinations of humeral heads with thickness to match our population. The glenoid width of females in our cohort was found to be smaller for the smallest size of the glenoid base plate. CONCLUSION: Smaller sized options in humeral head diameter and thickness of the anatomic prosthesis and glenoid baseplate of the reverse shoulder prosthesis need to be made available to suit our population and avoid a mismatch.

An outlook on procedures of conjugating folate to (co)polymers and drugs for effective cancer targeting.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.

Impact of COVID 19 lockdown on orthopaedic surgeons in India: A survey.

BACKGROUND: In the fight against COVID 19, the government of India announced a 3 weeks lockdown of the entire country of 1.3 billion people on 24th March 2020. METHODS: One week after the lockdown was announced, we conducted an anonymous online survey of the orthopaedic surgeons in India through social media platforms to assess the impact of the lockdown during COVID 19. The survey had a total of 13 questions with (3-5) options and was designed with an aim to understand the perception and the state of mind of the Orthopaedic surgeons in the lockdown situation. RESULTS: The survey was completed by 611 orthopaedic surgeons from 140 cities in India. There were 22.5% orthopaedic surgeons who said that they were definitely stressed out, and 40.5% who said they were mildly stressed out. As the age decreased, the percentage of orthopaedic surgeons feeling "definitely stressed out" increased. Disruption of life-work balance and uncertainties regarding return to work were other strongly associated factors with the "definitely stressed out" group. CONCLUSION: The psychological impact of the lockdown during COVID 19 on orthopaedic surgeons may become a potential concern that will require addressal through open discussion. LEVEL OF EVIDENCE: diagnostic level 4.